PROJECT SUMMARY/ABSTRACT The overall long-term objectives of this research are to: (1) reduce the over-prescribing of postoperative discharge opioids which contribute to the population reservoir of unused pills available for patient misuse, and for the diversion and misadventure which are contributing to the devastating public health problem of opioid addiction, overdose, and death; and (2) improve pain treatment, decrease postoperative opioid requirements, increase patient safety, and diminish opioid-related adverse and side effects after outpatient surgery. Our research fundamentally challenges long-practiced yet untested notions that opioids of short duration are the best way to treat surgical pain and to help patients. Anesthesiologists and surgeons face the challenge that surgical pain is inadequately treated in >80% of patients, 10-50% of whom develop chronic postsurgical pain, for which acute postoperative pain is the single greatest risk factor. Opioids are the primary pharmacotherapy for surgical pain, yet with increased use of short-duration opioids, surgical pain treatment has not improved over the past two decades. In contrast, three decades of clinical research and experience shows that a single intraoperative dose of a long-duration opioid (i.e. methadone), which sustains therapeutic drug concentrations, produces better analgesia than repeated doses of short-duration opioids and reduces further opioid requirements, in inpatient surgery. Nevertheless, in outpatient surgery, methadone has never been evaluated, and the potential benefits of methadone in outpatient surgery regarding better postoperative pain, side effects, safety, and reduced opioid consumption remain unrealized. This is a missed opportunity. We will test the innovative, paradigm-shifting hypothesis that in outpatient surgery, intraoperative anesthesia with methadone, compared with conventional short-duration opioids, achieves better analgesia, with similar or diminished side effects, reduces development of chronic postsurgical pain, improves postoperative recovery, and most importantly, decreases postoperative opioid consumption. Demonstrating reduced opioid consumption and hence diminishing prescribing of take-home opioids could shrink the population reservoir of unused opioids available for diversion and misuse, and reduce addiction, overdose, and death. This hypothesis will be tested in two prospective, randomized, double-blind clinical trials, with separate outpatient cohorts of short-stay (overnight <24 hours) and same-day surgery. We will compare general anesthesia with single-dose methadone vs as needed short-duration opioids, evaluate intraoperative and postoperative opioid use, opioid side effects, short-term and long-term postoperative pain, and overall quality of recovery for up to 1 year. Successful completion of the aims portends improved outpatient surgical care, enhanced patient recovery, and reduced postoperative opioid use. An ensuing revolutionary redesign of anesthesia care, and transformational approach to and reduction of postoperative opioid prescribing, would shrink the pool of prescription opioids in America, and help address one of the primary contributory factors to the opioid epidemic.